Process for preparing a specific diastereomer of a monoamino dicarboxylic acid ester

ABSTRACT

(Benzothiadiazine, benzamido and benzenesulfonyl)phenyl-substituted carboxyalkyl dipeptide compounds are disclosed. Compounds of this invention are useful as antihypertensive agents.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of application Ser. No. 651,378 filedSept. 17, 1984 and now U.S. Pat. No. 4,584,285 which is a continuationin part of application: Ser. No. 500,494 filed June 2, 1983 nowabandoned.

SUMMARY

The present invention relates to (benzothiadiazine, benzamido, andbenzenesulfonyl)-phenyl-substituted carboxyalkyl dipeptide compoundswhich have antihypertensive activity. Compounds of this invention areuseful as antihypertensive agents, in the treatment of congestive heartfailure and glaucoma. In addition, compounds of this invention areuseful as diuretics.

DETAILED DESCRIPTION

More particularly, this invention relates to compounds represented bythe following formula: ##STR1## wherein W is ##STR2##

n is 0 or 1; m is 0 to 2

p and q are each 0, 1 or 2, provided that the sum of p and q is 1 or 2,and that in formula V, p is not 0;

Y is --CH₂ --, --CH₂ O--, or --CH₂ S--, attached at the 2 or 4 positionof the phenyl group;

Z is ##STR3## wherein A is Cl or CF₃ ;

D is --(CH₂)_(u) --, --CH₂ --, --CH₂ S--; --CH₂ CNH--;

G is --CONR⁷ (CH₂)_(t) --, or --SO₂ NR⁷ (CH₂)_(t) --; t is 0 or 1;

R¹ and R⁴ are independently hydroxy, alkoxy having from 1 to 8 carbonatoms, K--X_(r) --(CH₂)_(s) --O--, wherein K is phenyl, substitutedphenyl, 1- or 2-naphthyl, X is oxygen or sulfur, r is 0 or 1 and s is 0or 4, and wherein the substitutents on the phenyl are chosen from groupM, wherein M is halogen, hydroxy, trifluoromethyl, alkoxy having from 1to 6 carbon atoms, alkyl from 1 to 6 carbon atoms, 2- and 3-furanyl, 2-and 3-thienyl and phenyl (which phenyl group may be substituted withhalogen, hydroxy, trifluoromethyl, alkoxy having from 1 to 6 carbonatoms or alkyl having from 1 to 6 carbon atoms), provided that when s iszero, r is zero, --OCH₂ --OCO-alkyl wherein the alkyl has from 3 to 8carbon atoms, --OCH₂ CO-- phenyl, wherein the phenyl may be substitutedwith group M, 1-glyceryl, ##STR4##

R², R⁵, R⁶ and R⁹ are hydrogen or lower alkyl;

R³ is hydrogen, lower alkyl or amino lower alkyl;

R⁷ is hydrogen, lower alkyl or phenyl(lower)alkyl;

R⁸ is hydrogen, lower alkyl, phenyl, or phenyl substituted by group M;

u is 1 or 2;

and the pharmaceutically acceptable salts thereof.

Preferred compounds of the invention are those wherein W is representedby formula III, IV or V. When W is of formula III or IV, preferredvalues for p and q are 0 and 1, respectively; when W is of formula V,preferred values of p, q and n are 1, 1 and 0 respectively.

Two additional groups of preferred compounds are that wherein R² and R⁵are hydrogen, and that wherein R⁴ is hydroxy.

Particularly preferred compounds are those wherein W is represented byformula III or V; n, p, q, Y, R², and R⁵ are as defined above forpreferred compounds; R³ is methyl or amino butyl; Z is of formula VI,wherein A is chlorine, or Z is of formula VII and G is -CONH-CH₂ - or--SO₂ NH--CH₂ ; R⁶ and R⁷ are hydrogen or methyl; and R¹ is hydroxy,ethoxy, methoxy, phenoxyethoxy, or pivaloyloxymethoxy.

As used herein, "lower alkyl" means straight or branched chainhydrocarbon radicals of from 1 to 6 carbons, e.g. methyl, ethyl, propyl,ispropyl, butyl, t-butyl, pentyl and hexyl. Similarly, "lower alkoxy"means straight or branched alkoxy radicals having 1 to 6 carbon atoms,e.g. methoxy, ethoxy, propoxy, butoxy, iso-butoxy, pentoxy and hexyloxy."Halogen" means fluorine, chlorine and bromine.

Compounds of the instant invention include various stereoisomers.Preferred stereoisomers are those in which the absolute configuration ateach of the three carbon atoms adjacent to both a nitrogen and acarbonyl group corresponds most closely to the absolute configuration ofL-amino acids.

The compounds of this invention form salts with various inorganic andorganic acids and bases which are also within the scope of theinvention. Such salts include ammonium salts, alkali metal salts, e.g.sodium and potassium salts, and alkaline earth metal salts, e.g. calciumand magnesium salts. Salts with organic and inorganic acids may beprepared, e.g., HCL, HBr, H₂ SO₄, H₃ PO₄, methanesulfonic acid,toluenesulfonic acid, maleic acid, fumaric acid and camphorsulfonicacid. The nontoxic pharmaceutically acceptable salts are preferred,although other salts are also useful, e.g., in isolating or purifyingthe product. The acid salts (e.g. HCl and maleate) are preferred,especially the hydrochloride.

The salts may be formed by conventional means, as by reacting the freeacid or base forms of the product with one or more equivalents of theappropriate base or acid in a solvent or medium in which the salt isinsoluble, or in a solvent such as water which is then removed in vacuoor by exchanging the cations of an existing salt for another cation on asuitable ion exchange resin.

Compounds of formula I may be prepared by several routes using methodsknown in the art.

For example, compounds of formula I may be prepared by condensing anamino acid of formula VIII with a keto compound of formula IX in thepresence of a reducing agent such as sodium cyanoborohydride in asolvent such as ethanol: ##STR5## wherein Z, Y, R¹, R², R³, R⁴, m and Ware as defined above.

Starting materials of formula VIII may be prepared by well knownmethods. An example of such a preparation is shown below, wherein5-(4-[6-chloro-7-sulfamoyl-3,4-dihydro-1,1-dioxo-1,2,4-benzothiadiazinyl3-)methoxy]benzyl)cysteine(formula XVI) is prepared, starting with 2-bromo-1,1-diethoxyethane andp-cresol: ##STR6##

Starting materials of formula IX may be prepared by reacting an aminoacid derivative XVIII with an α-keto acid chloride XVII to give thesubstituted amino acid: ##STR7## The reaction is carried out in an inertsolvent such as methylene chloride in the presence of a base such astriethylamine or pyridine.

Compounds of formula I wherein Y is --CH₂ --, and Z is a group offormula VII, are preferably prepared by the reaction of an acid offormula XIX with an amine of formula XX: ##STR8## wherein R¹, R³, R⁴, R⁶and W are as defined above, and "DEC" refers to1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl.

Compounds of formula XIX may be prepared from known starting materialsby techniques well known in the art. The following reaction schemedescribes a method of preparing a compound of formula XIX (designatedformula XIXa): ##STR9##

A preferred method for the conversion of compounds of formula XXII toXXIV in the reaction scheme above which eliminates the preparation ofdiastereomers of formula XXIII and their subsequent separation is to usethe specific diastereomer t-butyl 2R-(trifluoromethanesulfonyloxy)propionate (triflate reagent). In this novel process, the singlediastereomer of the triflate reagent reacts by nucleophillicdisplacement with the α-aminoacid ester (e.g., a compound of formulaXXII) to give a high yield of the corresponding specific singlediastereomer of the resulting monoamino dicarboxylic acid ester (e.g., acompound of formula XXIV).

Since the preferred compounds of formula I have an S-configuration atthe carbon to which R³ is attached the triflate reagent used herein isthe 2-R diastereomer (see Preparation 4). However, the process isgenerally applicable to converting a broad range of α-aminoacid estersto the desired specific single diastereomer by using the appropriatetriflate diastereomer. In place of the t-butyl ester of the triflate,other lower alkyl esters or the benzyl ester may be used.

The reaction proceeds at room temperature (i.e., 20°-50° C., preferablyabout 25° C.) in an inert solvent such as chloroform, dichloromethane,carbontetrachloride, benzene, toluene, or ethyl acetate in the presenceof a base such as a tertiary amine (e.g., triethylamine orN-methylmorpholine). The reaction is complete in about 24 hours or less.The desired compound is recovered from the reaction mixture and purifiedby standard techniques. For example, the crude product is extracted intoan organic solvent such as ether and concentrated to a crude oil, whichis then purified by column chromatography to yield the desired specificdiastereomer.

Carboxy-protected compounds of formula XX are prepared by methods wellknown in the art. See, for example, Neustadt et al. in European PatentApplication No. 50,800, published May 5, 1982.

Alternatively, compounds of formula I wherein Y is --CH₂ --, and Z is agroup of formula VII may be prepared by the reaction of an acid chlorideof formula XXVII with a dipeptide of formula XXVIII: ##STR10## whereinR¹, R³, R⁴, R⁶ and W are as defined above.

Compounds of formula XXVII may be prepared by known methods.

Compounds of formula XXVIII may be prepared by well known methods, anexample of which is shown in the following reaction scheme: ##STR11##

Alternatively, XXX may be hydrogenated directly to give XXVIIIa using acatalyst such as palladium on carbon.

Alternatively, XXXII may be reacted with a compound of formula XIXa togive a compound of formula I wherein R⁴ is benzyloxy. The benzyloxygroup may be then removed by hydrogenation with an appropriate catalystsuch as palladium on carbon.

The known coupling methods above include amino group protection duringthe coupling reaction, for example by N-formyl, N-t-butoxycarbonyl andN-carbobenzyloxy groups, followed by their removal to yield compounds offormula I. Furthermore, the COR⁴ function wherein R⁴ is OH may beprotected by removable ester groups such as benzyl, ethyl, t-butyl andthe like.

The more complex esters at R¹ (i.e., R¹ is other than hydroxy or alkoxy)are most conveniently prepared by esterifying compounds of formula Iwherein R¹ is hydroxy and R⁴ is benzyloxy with the appropriate reagent,then removing the benzyl ester at R⁴. For example, compounds of formulaI where R¹ is hydroxy and R⁴ is benzyloxy may be reacted withchloromethyl pivalate to obtain the corresponding pivaloyloxymethylester.

The following examples further illustrate the preparation of compoundsof this invention.

PREPARATION 1 1-Pyruvoyl-cis,syn-Octahydro-1H-Indole-2(S)-CarboxylicAcid

A. Dissolve 27.0 g of ethyl indole-2-carboxylate in 250 ml oftrifluoroacetic acid. Add 2.05 g of platinium oxide, hydrogenate themixture at 50 lb/in² at room temperature. Filter the mixture andconcentrate the filtrate in vacuo to give a residue. Suspend the residuein ether and treat with cold dilute sodium hydroxide solution. Dry theorganic layer over magnesium sulfate and concentrate it to give ethyloctahydroindole-2-carboxylate, a pale yellow oil.

B. Dissolve 116 g of 10-d-camphorsulfonic acid in 1 liter of warm ethylacetate and add a solution of 86 g of the product of part A in 1 literof ethyl acetate. Allow the mixture to crystallize, heat to reflux, coolto room temperature, and filter. Recrystallize the filter cake from amixture of 500 ml of isopropanol and 1800 ml ethyl acetate, filter anddry the crystals to obtain 2(S)-carboethoxy-cis,syn-octahydro-1H-indole,d-10-camphorsulfonate, m.p. 192°-193° C.

C. Slurry 10 g of the product of part B in 1 liter of ether, adjust topH 11 with aqueous sodium hydroxide, and stir for 5 minutes. Wash theorganic layer with sodium chloride solution, dry over magnesium sulfate,filter, and evaporate in vacuo at room temperature to obtain2(S)-carboethoxy-cis,syn-octahydro-1H-indole as a colorless oil.Dissolve the resultant oil in 50 ml of methanol containing 23 ml of 1Nsodium hydroxide, stir at 25° C. for 30 minutes, adjust to pH 7 with 1Nhydrochloric acid, and evaporate the solvent to givecis,syn-octahydro-1H-indole-2(S)-carboxylic acid.

D. Cool 23 ml of benzyl alcohol to 0° C. under nitrogen and add 5.95 gof thionyl chloride dropwise over 15 minutes, maintaining thetemperature at 0° C. Add the product of part C, stir for 1 hour at 0°C., then stir for 24 hours at room temperature. Pour the resultingmixture into 500 ml of ether, stir 1 hour under nitrogen, then allow tostand under nitrogen until the solution is clear. Decant thesupernatant, wash the precipitate with 25 ml of ether, then slurry theprecipitate in 200 ml of ether and adjust to pH 8-9 with 1-N sodiumhydroxide. Stir 5 minutes, wash the organic layer with sodium chloridesolution, dry over magnesium sulfate, filter and evaporate in vacuo atroom temperature to obtain cis,syn-octahydroindole -2(S)-carboxylicacid, benzyl ester as a colorless oil (TLC in ether: one spot, Rf 0.3).

E. To 26 g of the product of part D in 100 ml of dichloromethane and 7.8ml of pyridine add 11.0 g of pyruvoyl chloride and stir the resultingmixture at room temperature. Extract the reaction mixture with water anddry the organic layer over magnesium sulfate. Concentrate thedichloromethane solution in vacuo and distill the residue to give1-pyruvoyl-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid, benzylester.

F. To 20 g of the product from part E in 400 ml of ethanol, add 2.0 g of10% palladium-on-charcoal and hydrogenate at 50 psi at room temperature.Filter the resulting mixture and concentrate the filtrate in vacuo togive the title compound.

PREPARATION 21-{N-[1(S)-Ethoxycarbonyl-2-(4-aminophenyl)ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid Method I

A. To a solution of 4-nitrophenylalanine, ethyl ester, hydrochloride(54.0 g) in dry dimethylformamide (400 ml), add t-butyl2-bromopropionate (112.3 g) and triethylamine (76 ml) and heat theresulting mixture at 70° for 18 hours under a nitrogen atmosphere. Pourthe reaction mixture into water and extract with methylene chloride(6×300 ml). Combine the organic layers, dry over magnesium sulfate andconcentrate in vacuo to give a liquid (contains DMF). Chromatograph thisliquid on a Prep 500 (3 silica gel cartridges) using hexane (8 1) thenhexane:ethylacetate 4:1 and isolateN-[1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-(R)alanine, t-butylester, [α]_(D) ²⁶ =+24.7° (methanol), and N-1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-(S)alanine, t-butyl ester.

B. Add cold trifluoroacetic acid (600 ml) (ice bath) toN[1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-(S)-alanine, t-butyl ester(25.5 g) and stir the resulting mixture at room temperature under anitrogen atmosphere for 4 hours. Concentrate the solution in vacuo togive a viscous oil. Triturate the viscous oil with hexane (3 1) and thenether to yieldN-[1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-(S)-alanine.

C. To a solution of the product of Step B (17.84 g),cis,syn-octahydro-1H-indole-2(S)-carboxylic acid, benzyl ester (11.50g), and triethylamine (4.46 g) in dimethylformamide (450 ml) at 0°-5°under a nitrogen atmosphere, add 1-hydroxybenzotriazole (6.76 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (16.13 g).Stir the reaction mixture at 0°-5° for 25 minutes and then at roomtemperature for 90 minutes. Concentrate the reaction mixture in vacuoand partition between dichloromethane and saturated sodium bicarbonatesolution. Dry the organic layer over magnesium sulfate and concentratein vacuo to give a viscous oil which contains1-{N-[1(S)-ethoxycarbonyl-2(4-nitrophenyl)ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid, benzyl ester.

D. Hydrogenate the product from Step C above in absolute ethanol (250ml) in the presence of 10% palladium on carbon at 60 psi in a ParrShaker Apparatus. Remove the catalyst by filtration through celite andconcentrate the filtrate in vacuo to give a foam. Chromatograph the foamon the Prep 500 (3 cartriges) using chloroform:methanol:ammoniumhydroxide 200:30:5 as eluant to give the title compound [α]_(D) ²⁶=-44.0° (MeOH).

Method II

A. To a solution of 4-nitrophenylalanine, ethylester, hydrochloride (2.3g) in dichloromethane (10 ml), add triethylamine (2.55 ml) and thent-butyl 2(R)(trifluoromethanesulfonyloxy)propionate (2.80 g) (seePreparation 4) in dichloromethane (10 ml). Stir the resulting solutionat room temperature for 20 hours. Concentrate the reaction mixture, adddiethyl ether and extract with salt solution. Dry over magnesium sulfateand concentrate the ether solution in vacuo to give an oil. Place theoil on a column of silica gel (100 ml, 60-200 mesh) and elute withdiethyl ether:hexane 60:40 to giveN-[1(S)-ethoxycarbonyl)-2-(4-nitrophenyl)ethyl]-(S)-alanine, t-butylester.

B. to D. Proceed as described in Method I. PREPARATION 31-{N[1(S)-Ethoxycarbonyl-3-(4-aminophenyl)propyl]-(S)alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid Method I

A. To a solution of 2-acetamido-4-(4-nitrophenyl)butyric acid (57.65 g)in hot 95% ethanol (1000 ml) add d-(+)-α-methylbenzylamine (25.2 g) inhot 95% ethanol (125 ml), cool the solution slowly and keep at roomtemperature 18 hours. Collect the solid and wash with cold 95% ethanol,and dry to give an orange-yellow solid. Recrystallize this solid from95% ethanol treated with charcoal to give2(S)-acetamido-4-(4-nitrophenyl)butyric acid, d-(+)-α-methylbenzyl aminesalt [α]_(D) ²⁶ =+45.6 (MeOH), m.p. 211°-213° C.

B. Suspend the product of part A (29.00 g) in ether (500 ml) and add 1NNaOH (150 ml). Separate the aqueous solution and wash with ether. Coolthe aqueous solution in an ice-NaCl bath, add concentrated hydrochloricacid to pH 1 and stir the resulting mixture for 1 hour. Remove2(S)-acetamido-4-(4-nitrophenyl)butyric acid, a white solid, [α]_(D) ²⁶=+33.9° (MeOH), m.p. 266° C.

C. Treat the compound prepared in part B above (18.65 g) with 6Nhydrochloric acid (700 ml) and heat the resulting mixture under refluxfor 2.5 hours. Concentrate the solution in vacuo to give2(S)-amino-4-(4nitrophenyl)butyric acid, hydrochloride, a solid, m.p.186°-189° C., [α]_(D) ²⁶ =+46.9° (MeOH).

D. Heat the compound prepared in part C (19.30 g) in absolute ethanolsaturated with hydrogen chloride acid (400 ml) under reflux for 11/2hour. Remove the solvent in vacuo and triturate the residue with etherto give 2(S)-amino-4-(4-nitrophenyl)butyric acid, ethyl ester,hydrochloride, a white solid m.p. 288.5° [α]_(D) ²⁶ +40.6° (MeOH).

E. Treat the compound prepared in part D (18.00 g) in drydimethylformamide (250 ml) with t-butyl 2-bromopropionate (35.20 g) andtriethylamine (18.90 g) as described in Preparation 2A. Use Prep 500 (2cartridges) and hexane (6 1) and then hexane/ethyl acetate 8:1 aseluants and isolateN-[1(S)-ethoxycarbonyl-3-(4-nitrophenyl)propyl]-(S)-alanine, t-butylester [α]_(D) ²⁶ =-8.0° (MeOH).

F. To the product of part E (6.90 g) at 0°, add trifluoroacetic acid(500 g) and treat the resulting mixture as described in Preparation 2Band isolate N-[1(S)-ethoxycarbonyl-3-(4-nitrophenyl)propyl]-(S)alanine,trifluoroacetic acid salt, a viscous oil.

G. To a cold (0°-5° ) solution of the product of part F (6.68 g) andcis,syn-octahydro-1H-indole-2(S)-carboxylic acid, benzyl ester (3.95 g)in anhydrous dimethylformamide (250 ml) and triethylamine (3.38 g), add1-hydroxybenzotriazole (2.80 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (5.85 g) and stir the resultingmixture at 0°-5° C. for 30 minutes and then at room temperature for 1.5hour. Pour the reaction mixture into saturated sodium bicarbonate andextract with dichloromethane (2×1 l). Dry the organic layer overmagnesium sulfate and concentrate in vacuo to give a viscous oil.Chromatograph this oil on the Prep 500 (2 cartridges) using ethylacetate:hexane 3:20 and then 1:1 and isolate1-{N[1(S)-ethoxycarbonyl-3-(4nitrophenyl)propyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid, benzyl ester.

H. Hydrogenate the product of part G (4.69 g) in absolute ethanol (250ml) in the presence of 5% palladium-on-charcoal (0.50 g) at 60 psi in aParr Shaker Apparatus. Remove catalyst by filtration and concentrate thefiltrate to give the title compound, a foam [α]_(D) ²⁶ =-29.7° (MeOH).

Method II

A. to D. Proceed as described in Method I.

E. Treat the product of part D as described in Preparation 2, Method II,part A to obtainN-[1(S)-ethoxycarbonyl)-3-(4-nitrophenyl)propyl]-(S)-alanine, t-butylester.

F. to H. Proceed as described in Method I.

PREPARATION 4 t-Butyl 2R-(Trifluoromethanesulfonyloxy)Propionate

A. Add 2S-(p-toluenesulfonyloxy)propionic acid (4.4 g) to a coldsolution of 10 ml isobutylene and 0.4 ml concentrated sulfuric acid in30 ml methylene chloride in a pressure vessel, seal, and agitate at roomtemperaure for 48 hours. Pour into 50 ml 15% sodium carbonate solution,dry over magnesium sulfate and concentrate to obtain t-butyl2S-(p-toluenesulfonyloxy)propionate as an oil (NMR 1.37). Distilledmaterial (Kugelrohr, 120°) has [α]_(D) ²⁶ =-45.9° (EtOH, c=1).

B. Combine the product of part A (100 g) with acetic acid (40.0 g) andtriethylamine (67.2 g) in 200 ml dry DMF. Heat at 65° for 20 hours.Partition with 2 1 each ether and water, and wash the ether with citricacid, then with sodium bicarbonate solution. Dry and concentrate theether solution to obtain t-butyl 2R-acetoxypropionate as a colorlessliquid, bp 50° C./0.1 mm.

C. Combine the product of part B (62.6 g) with ethylenediamine (11.6 g)and heat at 70° for 24 hours. Allow to cool, add 300 ml ether andfilter. Wash the ether with water, 10% citric acid, and then in sodiumbicarbonate solution. Dry and concentrate the ether solution to leave acolorless oil. Crystallize from hexane at -20° to give t-butyl2R-hydroxypropionate as white needles, m.p. 41°-2° C.

D. Combine the product of part C (7.3 g) with pyridine (4.0 g) in 50 mlmethylene chloride. Cool to -5° C., and add dropwise a solution oftrifluoromethanesulfonic anhydride (14.1 g) in 25 ml methylene chloride.Allow the reaction to reach room temperature, then wash successivelywith water, 1N sulfuric acid and 1N sodium bicarbonate solution. Dry andconcentrate the methylene chloride solution to leave the title compoundas a colorless oil.

NMR (in CDC13)=5.10 q; 1.73 d; 1.50 s.

EXAMPLE 11-{N-[1(S)-Ethoxycarbonyl-2-[4-(3-sulfamoyl-4-chlorobenzamido)phenyl]ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid

To a 0°-5° C. solution of the product of Preparation 2 (2.00 g) inanhydrous tetrahydrofuran (100 ml) and triethylamine (0.94 g), add asolution of 4-chloro-3-sulfamoylbenzoylchloride (1.61 g) in anhydroustetrahydrofuran (10 ml) over a period of 30 minutes. Stir the resultingmixture for 15 minutes at 0°-5° and then at room temperature for 18hours. Filter the reaction mixture and concentrate the filtrate in vacuoto give a residue. Chromatograph the residue on the Prep 500 (1cartridge) using chloroform:methanol: ammonium hydroxide 200:30:5 aseluant to give the title compound, a foam, [α]_(D) ²⁶ -16.1° (MeOH).

In a similar manner, using appropriate starting materials, prepare thefollowing:1-{N-[1(S)-ethoxycarbonyl-2-[4-(4-chloro-3-N-methylsulfamoylbenzamido)phenyl]ethyl]-(S)-alanyl}-cis,syn-octahydro -1H-indole-2(S)-carboxylicacid, [α]_(D) ²⁶ =-18.7° (methanol).1-{N-[1(S)-ethoxycarbonyl-3-[4-(2-hydroxy-4-chloro-5sulfamoylbenzamido)phenyl]ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid, [α]_(D) ²⁶ =-18.1° (methanol).

EXAMPLE 21-{N-[1(S)-Carboxy-2-[4-(4-chloro-3-sulfamoylbenzamido)phenyl]ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid

To the product of Example 1 (0.35 g) add 0.5N NaOH (5 ml) and stir atroom temperature for 1 hour. Add Bio-Rad Resin (AG 50W-X3, 100-200 mesh,hydrogen form) and then add to a column of the same resin. Elute withwater (200 ml) and then water:pyridine 96:4. Concentrate the desiredfractions to give the title compound. [α]_(D) ²⁶ =-7.0° (MeOH).

In a similar manner, prepare1-{N[1(S)-carboxyl2-[4-(4-chloro-3-N-methylsulfamoylbenzamido)phenyl]ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid, [α]_(D) ²⁶ =8.9° (methanol).

EXAMPLE 31-{N-[1(S)-Ethoxycarbonyl-3-[4-(4-chloro-3sulfamoylbenzamido)phenyl]propyl]-(S)-alanyl}-cis,synoctahydro-1H-indole-2(S)-carboxylic acid

To a 0°-5° solution of the compound of Preparation 3 (1.50 g) inanhydrous tetrahydrofuran (100 ml) and triethylamine (0.68 g), add asolution of 4-chloro-3-sulfamoylbenzoylchloride (1.11 g) and treat asdescribed in Example 1, except use chloroform (2 1) and thenchloroform:methanol:ammonium hydroxide100:30:5 as eluants and isolatethe title compound, a foam [α]_(D) ²⁶ =-9.1 (methanol).

In a similar manner using appropriate starting materials, prepare1-{N-[1(S)-Ethoxycarbonyl-3-[4-(4-chloro-3-N-methylsulfamoylbenzamido)phenyl]propyl]-(S)-alanyl}cis,syn-octahydro-1H-indole-2(S)-carboxylicacid.

EXAMPLE 41-{N-[1(S)-Carboxy-2-([4-{(6-Chloro-3,4-Dihydro-7-Sulfamyl-2H-1,2,4-Benzothiadiazin-3-yl-1,1-Dioxide)Methyloxy]Phenyl]Methylthioethyl)-(S)-Alanyl}-cis,syn-Octahydro-1H-Indole-2(S)-CarboxylicAcid

A. Combine bromoacetaldehyde diethylacetal (19.7 g) and p-cresol (10.8g) in dry dimethylformamide (DMF) (100 ml) and stir. Add potassiumt-butoxide (9.6 g) and continue stirring for 24 hours, then evaporatethe DMF in vacuo. Partition the resultant residue between ethyl acetateand water. Separate the organic layer, wash with 10% aqueous sodiumhydroxide followed by brine, then dry the organic layer over sodiumsulfate and filter. Evaporate the solvent in vacuo and purify the crudeproduct on a silica gel column to obtain 4-[2,2diethoxy)ethoxy]toluene:

NMR δ=1.12 (6H, t,CH₃); 2.15 (s, 3H,--CH₃); 3.55 (q 4H, CH₂ --O );3.90(d, 2H, CH₂ phenyl); 4.77 (t,1H, --CH₂ --); and 6.80 (m, 4H, Ar).

B. Combine N-bromosuccinamide (0.877 g) and the product of Step A (1 g)in carbon tetrachloride (20 ml) and stir at reflux for 18 hours. Filterthe resultant solid and evaporate the solvent in vacuo to obtain4-[(2,2-diethoxy)ethoxy]benzyl bromide:

NMR=1.10 (t, 6H, CH); 3.59 (q, 4H, --OCH₂); 3.86 (d, 2H, C--CH₂);4.31(s, 2H, CH₂ --Br); 4.70 (t, 1H, --CH--); 7.00 (m, 4H, Ar).

C. Combine methyl alcohol (20 ml) and 19 M sodium hydroxide (10 ml). AddL-cysteine (0.1 g), stir for 15 minutes, then add the product of Step Band stir at room temperature overnight. Adjust the resultant solution toapprox. pH 7 and filter the resultant solid. Wash the solid with etherand dry under vaccum to obtain(S)-{4-[(2,2-diethoxy)ethoxybenzyl]cysteine.

D. Dissolve 4-amino-6-chloro-1,3-benzenedisulfonamide (0.74 g) indimethoxyethane (10 ml), add the product of Step C (0.99 g), stir whileheating to reflux, and add 2 drops of concentrated hydrochloric acid.Reflux 4 hours, then evaporate the solvent in vacuo. Wash the resultantsolid with ether and dry under vacuum to obtainS-[4-[(6-chloro-3,4-dihydro-7-sulfamyl2H-1,2,4-benzothiadiazin-3-yl-1,1-dioxide)methoxy]benzyl-L-cysteine.

E. React 0.02 moles of the product of part D in 20 ml of tetrahydrofuranwith 0.02 moles of the product of Preparation 1 and add 20 ml ofmolecular sieves 4A (Rohm and Haas). Stir the resulting mixture for 4hours, add 12 g of sodium cyanoborohydride in 20 ml of methanol and stirthe reaction mixture 20 hours. Filter, concentrate to dryness, andpartition the residue between water and dichloromethane. Absorb theaqueous phase on strong acidic ion-exchange resin and elute with 4%pyridine in water. Separate the isomers on a column of silica gel usingCHCL₃ : isopropanol: 7% ammonium hydroxide 1:1:1 (organic phase) aseluant to give the title compound.

EXAMPLE 51-{N-[1(S)-Ethoxycarbonyl-2-[4-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)phenyl]ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid

A. Hydrogenate a solution ofN-[1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl? -(S)-alanine, t-butylester (20.0 g) (see Preparation 2, IA) in absolute ethanol (500 ml) inthe presence of 10% palladium on carbon (1.5 g) at 50 psi in a Parrshaker apparatus. Remove the catalyst by filtration and concentrate thefiltrate in vacuo to giveN-[1(S)-ethoxycarbonyl-2-(4-aminophenyl)ethyl]-(S)-alanine, t-butylester.

B. To a solution of the product of part A in dimethylformamide (150 ml),add6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-aceticacid (14.4 g), 1-hydroxybenzotriazole (6.8 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (9.6 g) at0°-5° . Warm the reaction mixture to room temperature and stir for 18hours. Concentrate the reaction mixture in vacuo, add dichloromethaneand concentrate in vacuo. Dissolve the residue in ethyl acetate andextract with 1N sodium bicarbonate. Dry (MgSO4) and concentrate theethyl acetate solution in vacuo. Chromatograph the residue on silica gelusing the Waters Prep 500 using ethylacetate as eluant to giveN1(S)-ethoxycarbonyl-2-[4-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)phenyl]ethyl]-(S)-alanine,t-butyl ester.

C. Treat the product (11.0 g) prepared in Example 5B with dioxanesaturated with hydrogen chloride (100 ml) for 20 hours at RT.Concentrate the reaction mixture in vacuo and tritrate the residue withanhydrous ether to isolateN-[1(S)-ethoxycarbonyl-2-[4-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3acetamido)phenyl]ethyl-(S)-alaninehydrochloride salt.

D. Treat the product of part C as described in Preparation 2I, C toobtain {1-N-[1(S)-[ethoxycarbonyl2-[4-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)phenyl]ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid, benzyl ester.

E. Treat the product (7.3 g) of part D with 20% HBr in glacial aceticacid (30 ml) at 0°-5° and then stir at room temperature for 3 hr.Concentrate the reaction mixture in vacuo and wash the residue withether to give the title compound, hydrobromide.

F. Treat the product (3.0 g) of part E with Bio-Rad Resin (AG 50W-X2,100-200 mesh) in water and then add to a column of the same resin. Elutewith water, then water:pyridine 96:4 and then water:pyridine: absoluteethanol 76:20:4. Concentrate the fractions (iodine positive) in vacuo togive the title compound.

EXAMPLE 61-{N-[1(S)-Carboxy-2-[4-(6-chloro-3,4-dihydro-1,1-dioxo7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)phenyl-]ethyl]-(S)-alanyl}cis,syn-octahydro-1H-indole-2(S)carboxylicacid

To the product from Example 5 (3.0 g) add 1N NaOH (20 ml) and treat asdescribed in Example 2 to give the title compound.

EXAMPLE 71-{N-[1(S)-Ethoxycarbonyl-3-[4-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3acetamido)phenyl]propyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid

Treat the product of Preparation 3IE as described in Example 5 toproduce the title compound.

EXAMPLE 81-{N-[1(S)-Carboxy-3-[4-(6-chloro-3,4-dihydro-1,1-dioxo7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)phenyl]propyl]-(S)-alanyl}cis,syn-octahydro-1H-indole-2(S)carboxylicacid

Treat the product of Example 7 as described in Example 2 to produce thetitle compound.

By following the procedures described in the above preparations andexamples, and by using the appropriate reagents, the following compoundsmay be prepared:

1-{Nα-[1(S)-ethoxycarbonyl-3-[4-(6-chloro-3,4-dihydro1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)phenyl]propyl]-(S)-lysyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid;

1-{N-[1(S)-methoxycarbonyl-4-[4-(6-chloro-3,4-dihydro1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)phenyl]butyl]-(S)-alanyl}cis,syn-octahydro-1H-indole-2(S)-carboxylicacid;

2-{N-[1(S)-ethoxycarbonyl-3-[4-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)phenyl]propyl]-(S)-alanyl}-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxlicacid;

1-{N-[1(S)-(2-phenoxyethoxycarbonyl)-3-[4-(4-chloro-3sulfamoylbenzamido)phenyl]propyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid;

1-{N-[1(S)-pivaloyloxymethoxycarbonyl)-3-[4-(4-chloro-3sulfamoylbenzenesulfonamido)phenyl]propyl]-(S)alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid;

1-{N-[1(S)-ethoxycarbonyl-3-[4-(6-chloro-3,4-dihydro-1,1-dioxo-2-methyl-7-methylsulfamoyl-1,2,4-benzothiadiazine3-acetamido)phenyl]propyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid;

1-{N-[1(S)-ethoxycarbonyl-3-[4-(4-chloro-3-sulfamoylbenzenesulfonamido)phenyl]propyl]-(S)-alanyl}-(S)-proline;

1-{N-[1(S)-carboxy-3-[4-(6-chloro-3,4-dihydro-1,1-dioxo7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)phenyl]propyl]-(S)-alanyl}-(S)-proline;

7-{N-[1(S)-carboxy-3-[4-(6-chloro-3,4-dihydro-1,1-dioxo7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)phenyl]propyl]-(S)-alanyl}-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylicacid;

7-{N-[1(S)-carboxy-3-[4-(4-chloro-3-sulfamoylbenzamido)phenyl]propyl]-(S)-alanyl}-1,4-dithia-7-azaspira[4.4]-nonane-8(S)-carboxylicacid;

2-{N-[1(S)-carboxy-3-[4-(4-chloro-3-sulfamoylbenzenesulfonamido)phenyl]propyl]-(S)-alanyl}-1,2,3,4-tetra-hydroisoquinoline-3(S)-carboxylicacid;

1-{N-[1(S)-ethoxycarbonyl-4-[2-(6-trifluoromethyl-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazinyl-3acetamido)phenyl]propyl]-glycyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid;

1-{N-[1(S)-ethoxycarbonyl-2-[4-(6-chloro-3,4-dihydro-2-benzyl-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3acetamido)phenylthio]ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid;

1-{N-[1(S)-ethoxycarbonyl-2-[4-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-2-benzyl-3acetamido)phenyl]methoxyethyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid;

1-{N-[1(S)-ethoxycarbonyl-3-[4-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazin-3-yl)methylthiophenyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid;

The compounds of this invention are useful in view of theirpharmacological properties. In particular, they possess activity asantihypertensive agents, as evidenced by their ability to reduce bloodpressure in mammals in which the blood pressure has become abnormallyelevated.

Since these compounds are believed to act as angiotensin convertingenzyme inhibitors, it is also contemplated that they may be used intreating other cardiovascular disorders, for example congestive heartfailure, and glaucoma in the same manner as other ACE inhibitors such ascaptopril and enalapril may be used.

The compounds of this invention can be combined with pharmaceuticalcarriers and administered in a variety of well-known pharmaceuticalforms suitable for oral or parenteral administration to providecompositions useful in the treatment of cardiovascular disorders andparticularly mammalian hypertension.

The effective daily antihypertensive dose (ED50) of the compounds ofthis invention will typically be in the range of about 0.1 to about 25mg/kg, of mammalian weight, administered in single or divided doses. Theexact dose to be administered in determined by the attending clinicianand is dependent upon where the particular compound lies within theabove quoted range, as well as upon the age, weight and condition of theindividual.

Generally, in treating humans having hypertension, the compounds of thisinvention may be administered to patients in need of such treatment in adosage range of about 5 to about 500 mg per patient generally givenseveral times a day, thus giving a total daily dose of from about 5 toabout 2000 mg per day.

The antihypertensive compositions containing the compounds of thisinvention will preferably contain from about 5 to about 250 mg of theactive compound per dosage unit.

The compositions of the present invention are most preferablyadministered orally. Typical formulations for oral administration arethose such as tablets, capsules, syrups, elixiers or suspensions.Typical injectable formulations include solutions and suspensions. Alsocontemplated are mechanical delivery systems, e.g. transdermal dosageforms.

The typical acceptable pharmaceutical carriers for use in theformulation described above are exemplified by: sugars such as lactose,sucrose, mannitol and sorbitol; starches such as corn starch, tapiocastarch and potato starch; cellulose and derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and methyl cellulose; calciumphosphates such as dicalcium phosphate and tricalcium phosphate; sodiumsulfate; calcium sulfate; polyvinylpyrrolidone, polyvinyl alcohol;stearic acid; alkaline earth metal stearates such as magnesium stearateand calcium stearate, stearic acid, vegetable oils such as peanut oil,cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationicand anionic sufactants; ethylene gylcol polymers; beta-cyclodextrin;fatty alcohols and hydrolyzed cereal solids; as well as other non-toxiccompatible filters, binders, disintegrants, buffers, preservatives,anti-oxidants, lubricants, flavoring agents, and the like commonly usedin pharmaceutical formulations.

In the following examples, the "active ingredient" is1-{N-[1(S)-ethoxycarbonyl-3-[4-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-2H-1,2,4benzothiadiazine)acetamido]phenyl]propyl]-(S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylicacid. It is contemplated, however, that this compound may be replaced byequally effective quantities of other compounds within the scope offormula I.

EXAMPLE 10

    ______________________________________                                        Capsule            Amount (mg)                                                ______________________________________                                        Active ingredient  250.0   125.0                                              Lactose            173.0   86.5                                               Corn Starch        75.0    37.5                                               Magnesium stearate 2.0     1.0                                                                   500.0   250.0                                              ______________________________________                                    

Blend the active ingredient, lactose, and corn starch until uniform;then blend the magnesium stearate into the resulting powder. Encapsulatethe mixture into suitably sized two-piece hard gelatin capsules.

EXAMPLE 11

    ______________________________________                                        Tablet          Amount (mg)                                                   ______________________________________                                        Active Ingredient                                                                             250.0      125.0                                              Lactose         161.0      80.5                                               Corn Starch     12.0       6.0                                                Water           120 ml     60 ml                                              (per thousand tablets)                                                                        (evaporates)                                                                             (evaporates)                                       Corn Starch     75.0       37.5                                               Magnesium Stearate                                                                            2.0        1.0                                                                500.0      250.0                                              ______________________________________                                    

Blend the active ingredient with the lactose until uniform. Blend thesmaller quantity of corn starch with the water and add the resultingcorn starch paste, then mix until a uniform wet mass is formed. Add theremaining corn starch to the remaining wet mass and mix until uniformgranules are obtained. Screen the granules through a suitable millingmachine, using a 3/4 inch stainless steel screen. Dry the milledgranules in a suitable drying oven until the desired moisture content isobtained. Mill the dried granules through a suitable milling machineusing a 16 mesh stainless steel screen. Blend in the magnesium stearateand compress the resulting mixture into tablets of desired shape,thickness, hardness and disintegration.

EXAMPLE 12

    ______________________________________                                        Injectable Solution mg/ml                                                     ______________________________________                                        Active ingredient   5.00                                                      Methyl  -p-hydroxybenzoate                                                                        0.80                                                      Propyl  -p-hydroxybenzoate                                                                        0.10                                                      Disodium Edetate    0.10                                                      Citric Acid Monohydrate                                                                           0.08                                                      Dextrose            40.0                                                      Water for injection qs. ad.                                                                       1.0 ml                                                    ______________________________________                                    

Dissolve the p-hydroxybenzoates in a portion of water for injection at60°-70° C. and cool the solution to 25°-25° C. Charge and dissolve allother excipients and the active ingredient. Bring the solution to finalvolume, filter it through a sterilizing membrane and fill into sterilecontainers.

Similarly, substitute other compounds of the present invention toprepare other compositions of the present invention.

We claim:
 1. A process for the preparation of a single diastereomer ofan monoamino dicarboxylic acid which comprises reacting an ? -aminoacidester with a lower alkyl or benzyl ester of a specific diastereomer of2(trifluoromethanesulfonyloxy) propionic acid at room temperature in aninert solvent in the presence of a base to obtain the correspondinglower alkyl or benzyl ester of the resulting monoamino dicarboxylic acidas a specific diastereomer.
 2. A process according to claim 1 whereinthe α-aminoacid ester is reacted with t-butyl2(R)(trifluoromethanesulfonyloxy)propionate to give the corresponding2(S)-aminoacid, t-butyl ester.
 3. A process according to claim 2 whereinthe α-aminoacid ester is p-nitro-L-phenylalanine, ethyl ester, and theproduct is N-[1(S)-ethoxycarbonyl-2-(4nitrophenyl)ethyl]-(S)-alanine,t-butyl ester.